MTM1 p.Gln451=
c.1353G>A · rs587783781 · VCV158923
ClinGen expert panel — Congenital Myopathies VCEP
Likely Pathogenic for centronuclear myopathy. Applied ACMG criteria (verbatim):
PM6 PM2_Supporting PS4_Moderate PP3
Curation rationale (ClinGen, verbatim)
The NM_000252.3:c.1353G>A variant in MTM1 is a synonymous variant (p.Gln451=) located near the canonical donor site of intron 12. The variant is absent from gnomAD v4.1.0 meeting PM2_Supporting. The silent variant is predicted to impact splicing by SpliceAI (PP3). This variant has been reported in at least three probands, one with myotubular myopathy, one with congenital myopathy and abnormal muscle biopsy, and another with neonatal hypotonia. One of the three was a de novo occurrence with unconfirmed parental relationships (PS4_Moderate, PM6; PMID: 10790201; LabCorp, ClinVar: SCV001391223.5). In summary, the variant meets the criteria to be classified as likely pathogenic for X-linked centronuclear myopathy. ACMG/AMP criteria met, as specified by the ClinGen Congenital Myopathies VCEP: PS4_Moderate, PM6, PM2_Supporting, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1.0.0; 1/13/2025).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.87 | donor loss · deltas |
|---|---|---|
| Pangolin | Δ0.75 | loss · gain 0.00 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 0.98, phastCons 1 |
| Overall | ||
| CADD | 17.73 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- MTM1
- Protein
- p.Gln451=
- Coding
- c.1353G>A
- MANE Select
- NM_000252
- dbSNP
- rs587783781
- Type
- single nucleotide variant
- Location
- chrX:150659756 (GRCh38)
- Structure
- AlphaFold pLDDT 90.10
- Residue 451
- the myotubularin phosphatase domain
Similar variants
- MTM1 c.1644+1G>A Pathogenic ★★★ same condition
- MTM1 p.Arg224Ter Pathogenic ★★★ same condition
- MTM1 p.Arg69Cys Pathogenic ★★★ same condition
- MTM1 p.Glu404Lys Pathogenic ★★★ same condition
- MTM1 p.Pro205Leu Pathogenic ★★★ same condition
- MTM1 p.Trp230Arg Likely pathogenic ★★★ same condition
- MTM1 p.Trp230Cys Likely pathogenic ★★★ same condition
- MTM1 p.Tyr192Cys Likely pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mtm1-p-gln451 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown